Antibody-Mediated Immune Suppression of Fetal and Neonatal Alloimmune Thrombocytopenia ( FNAIT)

Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) is a severe alloimmune disorder caused by maternal anti-platelet antibodies traversing placenta, sensitizing fetal antigen positive platelets which are removed from the fetal circulation causing fetal thrombocytopenia and risk of hemorrhage. Intracranial bleeding and death of the newborn or survival with severe disability are the most feared complications. The mother may be immunized by fetal platelet antigens during pregnancy or in connection with delivery. So far, 17 such antigen systems implicated in FNAIT have been identified, included HPA-1a antigen that is located throughout the extracellular part of the P3 integrin subunit (GPIIIa) on aIIbp3 (GPIIbIIIa) the most abundant platelet receptor. European data show that the risk of FNAIT is about one in 1000-2000 pregnancies. Scientific rationale strongly suggests that prophylaxis using anti-HPA immunoglobulin G (IgG) could, through antibody mediated immune suppression (AMIS), prevent platelet alloimmunization in women. Obvious pathological similarities indeed exist between FNAIT and hemolytic disease of the fetus and newborn (HDFN), in which the alloantibodies are directed towards the D antigen present on red cells. Prophylaxis using human plasma-derived anti-D IgQ a product on the WHO Model List of Essential Medicine, is the most widespread and successful clinical application of AMIS. Anti-HPA IgG preparation may have a similar potential clinical benefit to prevent FNAIT. This project is conducted in partnership with Tromso University (Norway), the most advanced group in the world in the development of a treatment to prevent FNAIT. Our objective here is first to develop a state-of-the-art purification and viral inactivation process of human IgG that could be used for anti-HPA production. The developed process will be evaluated for the purification of polyclonal anti-HPA IgG from various plasma donations (collected in Norway from previously alloimmunized women) and from genetically-engineered HEK293 cells expressing an anti-HPA monoclonal antibody. The therapeutic efficacy of the different preparations to prevent alloimmunization will be assessed in transgenic mice models of FNAIT, allowing comparison of efficacy and the required dosage of both polyclonal and monoclonal preparations to induce AMIS and therefore prevent FNAIT. The data obtained in this project will pave the way for a future scale-up of the manufacturing process of clinical grade anti-HPA IgQ including anti-HPA-1a and other specificities of relevance to Taiwanese and Asian populations, eventually allowing to conduct clinical trials designed to assess safety and efficacy to prevent alloimmunization in humans.